tbuckley/cabot-search huggingface dataset:
Relative disclosure of information on hereditary cancer syndromes: A systematic review and meta-analysis.
Authors: Muhammad Danyal Ahsan, Hannah Bergeron, Jenny Lin, Priyanka Narayan, Becky Baltich Nelson, Xuan Li, Charlene Thomas, Paul J. Christos, Eloise Chapman-Davis, Evelyn Cantillo, Kevin Holcomb, Ravi Sharaf, Melissa Kristen Frey
Journal: Journal of Clinical Oncology (2022)

10592 Background: Evidence-based guidelines recommend that patients (probands) diagnosed with a hereditary cancer syndrome share the information with blood relatives as relatives can have 50% risk for harboring the same pathogenic mutation. This information offers the opportunity for relatives to undergo genetic counseling, genetic testing, early detection, and prevention of cancer. Limited literature on this topic suggests underutilization of recommended family member disclosure. We sought to evaluate rates of familial disclosure of hereditary cancer syndrome information in the first meta-analysis on this topic. Methods: We conducted a systematic review and meta-analysis in accordance with PRISMA guidelines (PROSPERO no.: CRD42020134276). We searched key electronic databases to identify studies evaluating hereditary cancer cascade relative disclosure. Eligible trials were subjected to meta-analysis. Results: Thirty studies met inclusion criteria. This review included 3,779 probands and 12,751 at-risk relatives. Among 12,751 included relatives, 72% (CI 64-79%) received information about the hereditary cancer syndrome identified in their family and 28% (CI 19-37%) underwent genetic testing. On meta-analysis, there was a higher rate of disclosure among female vs male relatives (79% [73% - 84%] vs 67% [57% - 75%]) and a higher rate among first-degree vs. second degree relatives (83% [77% - 88%] vs 58% [45 – 69%]). The data regarding the contribution of race/ethnicity to disclosure were limited and inconsistent, with two studies demonstrating non-White vs. White relatives being less likely to have results disclosure and two studies finding no correlation; however, both studies finding no difference were limited by small sample sizes. Finally, one study found that higher proband annual income was associated with improved familial disclosure. Conclusions: Despite a growing understanding of the importance of cascade genetic counseling and testing, probands do not disclosure information on hereditary cancer syndromes to most at-risk relatives. Very few relatives complete genetic testing, representing a critical missed opportunity for precision cancer prevention. Future studies are needed to elucidate barriers to hereditary cancer syndrome disclosure and create innovative strategies to facilitate this essential process.
Use of clinical RNA-sequencing in the detection of actionable fusions compared to DNA-sequencing alone.
Authors: Jackson Michuda, Ben Ho Park, Amy Lauren Cummings, Siddhartha Devarakonda, Bert O'Neil, Sumaiya Islam, Jerod Parsons, Rotem Ben-Shachar, Alessandra Breschi, Kimberly L. Blackwell, James Lin Chen, Joel Dudley, Martin Stumpe, Justin Guinney, Ezra E.W. Cohen
Journal: Journal of Clinical Oncology (2022)

3077 Background: While targeted DNA-seq can detect clinically actionable fusions in tumor tissue samples, technical and analytical challenges may give rise to false negatives. RNA-based, whole-exome sequencing provides a complementary method for fusion detection, and may improve the identification of actionable variants. In this study, we quantify this benefit using a large, real-world clinical dataset to assess actionable fusions detected from RNA in conjunction with DNA profiling. Methods: Using the Tempus Research Database, we retrospectively analyzed a de-identified dataset of ̃80K samples (77.4K patients) profiled with the Tempus xT assay (both DNA-seq with fusion detection in 21 genes and whole exome capture RNA-seq). Only patients that had successful RNA- and DNA-seq were included. Fusions were detected using the Tempus bioinformatic and clinical workflow. Candidate fusions were filtered based on read support thresholds, fusion annotation ( i.e., breakpoints, reading frame, conserved domains), and manual review. OncoKB was used to select fusion alterations in levels 1 and 2 and to identify those indication-matched to targeted therapies. Results: We identified 2118 level 1 and 2 fusion events across 1945 patients across 20 different cancer types. Most fusions were observed in non-small cell lung cancer (NSCLC) (25%) and biliary cancer (9%) samples. Of the 2118 fusion events, 29.1% (616) were detected only through RNA-seq while 4.8% (101) of the events were identifiable only through DNA-seq. Notably, 69.4% of fusions in low-grade glioma and 58.2% in sarcomas were detected only by RNA-seq. When evaluating specific gene fusion events, RNA-seq consistently improved the detection of fusions compared to DNA-seq alone (Table) across all cancer types. A total of 1106 fusions were classified as targetable by OncoKB indication-matched therapies with 19% (214) of these identifiable through RNA-seq alone, 5% (54) by DNA-seq alone, and 76% (838) identifiable through RNA- and DNA-seq. Overall, fusions identified through RNA-seq alone led to a 24% increase in the number of patients who were eligible to receive matched therapies (214 / 892). This included imatinib for patients with CML/BLCL (69.8%), crizotinib for NSCLC (40.3%) and entrectinib for NTRK and ROS1 fusions (32.5%). Conclusions: The addition of RNA-seq to DNA-seq significantly increased the detection of fusion events and ability to match patients to targeted therapies. Results support consideration of combined RNA-DNA-seq for standard-of-care fusion calling. [Table: see text]
Spatial transcriptomics unravels novel signaling patterns at the leading edge of oral squamous cell carcinoma.
Authors: Rohit Arora, Christian Cao, Mehul Kumar, Ayan Chanda, Divya Samuel, Wayne Matthews, Shamir Chandarana, Robert Hart, Joseph C. Dort, Martin Hyrcza, Pinaki Bose
Journal: Journal of Clinical Oncology (2022)

e18043 Background: Head and neck cancer is the 6th most common cancer worldwide. Oral squamous cell carcinoma (OSCC) is the most prevalent head and neck cancer that is characterized by aggressive local invasion and metastasis. Despite the leading edge (invasive front) of the tumor being a driver of OSCC pathophysiology, its biology and clinical relevance have not been fully characterized. We used spatial transcriptomics to explore signaling patterns within the leading edge and tumor core. Methods: Fresh-frozen, surgically resected OSCC samples from three HPV-negative OSCC patients were profiled using the 10x Genomics Visium Spatial Gene Expression platform. Leading edge and tumor core regions were defined by pathologist annotations and expression of previously identified edge and core gene signatures from the literature. Spatial differential gene expression (DGE) analysis and pathway analysis was performed using the Seurat package and Ingenuity Pathway Analysis (IPA), respectively. Cell-cell interaction networks were reconstructed using the CellChat package. Results: The leading edge and tumor core displayed unique transcriptional and signaling profiles that were conserved across all three OSCC patient samples. DEG analysis revealed 31 genes enriched in the leading edge and 62 genes enriched in the tumor core with a log2FC &gt; 0.58 and adjusted p-value &lt; 0.01. The top genes upregulated in the leading edge were FN1, COL1A1, COL1A2, IFITM3, and SPARC. Top tumor-core genes included CRCT1, LCE3D, DEFB4A, SPRR2A, and CNFN. IPA analysis of upregulated DEGs in the leading edge and tumor core predicted the activation of wound healing and GP6 signaling pathways, and activation of intrinsic prothrombin activation and MSP-RON signaling pathways, respectively. Cell communication analysis revealed that the leading edge had higher intercellular signaling than the tumor core. Upregulated leading edge cell signaling modules included collagen, CD99, CSPG4, and non-canonical WNT pathways, which have been linked to tumor invasion, metastasis, and adhesion. COL1A1 and COL1A2 ligands and CD44 and SDC1 receptors were upregulated in leading edge signaling. The tumor core was enriched for ANGPTL and PERIOSTIN cell signaling modules. Conclusions: This is the first study to characterize the tumor core and leading edge of OSCC tumors using spatial transcriptomics. Further investigation of the therapeutic potential of identified signaling pathways may improve OSCC outcomes.
Long-term impact of postnatal overfeeding on cardio-metabolism risk and on sensitivity to ischemia-reperfusion injury in vivo
Authors: E Rigal, MJ Josse, GD Dogon, IP Porcherot, LR Rochette, CG Guenancia, CV Vergely
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Nutritional disturbances during the postnatal period may be responsible for a predisposition, or "programming", to increased cardio-metabolic risk and to a progressive alteration of left ventricular contractility in adulthood. However, these data have mainly obtained in young male mice, but less is known for older animals. Purpose Our aim was to evaluate the impact of postnatal overfeeding (PNOF) on cardiac function, on cardiac sensitivity to ischemia-reperfusion (I-R) injury in vivo and on glucose metabolism in young (4 months), adult (6 months) and old (12 months) male mice. Methods PNOF was induced by the reduction of litter size of C57/BL6 mice immediately after birth: normally-fed group (NF) was composed of 9 male pups/mother and overfed group (OF) of 3 pups/mother. Echocardiography and blood sugar tests (glucose tolerance and insulin resistance) have been performed at all ages. An in vivo ischemia-reperfusion injury was induced by the ligation of the anterior interventricular artery for 45 minutes followed by 24 h of reperfusion. All experiments have been done on 4-, 6- and 12-months aged male mice. Results PNOF induced an early and permanent increase in body weight in OF group, independently of mice’s age (+23% at 24 days of life, +14% at 4 months, +23% at 6 and 12 months, compared to NF group). The echocardiographic measurements showed an alteration of contractile function from 6 months aged males and up to 12 months as evidenced by a decrease of the left ventricular ejection fraction (-11 % for OF males from 6 to 12 months, compared to NF groups). These cardiac alterations were associated with glucose metabolism imbalance: OF males presented glucose intolerance and insulin resistance from 4 to 12 months of age. To finish, PNOF induced a significant increase of infarct size at 4 months (+37%, p&amp;lt;0.01, n=8), 6 months (+32%, p&amp;lt;0.05, n=9) and 12 months (+38%, p&amp;lt;0,05, n=9) after cardiac surgery. Conclusion Nutritional programming through short-term PNOF induced an early alteration of glucose metabolism and was associated with a constant higher susceptibility to myocardial I-R injury in vivo. Moreover, mice which were submitted to PNOF developed altered cardiac contractility at 6 months and up to 12 months. The cellular and biochemical mechanism of these pathological modifications induced by PNOF need further exploration but could involve alterations in cardiomyocyte pathways, and/or modification of global inflammatory status.
Management of Patients With Nonmetastatic Prostate Cancer
Authors: Julio M. Pow-Sang
Journal: Journal of the National Comprehensive Cancer Network (2022)

Localized prostate cancer is a heterogeneous disease. However, some diagnostic features are helpful in categorizing patients into risk groups for adverse outcomes, such as pathology, imaging, and genetic profiling. Risk‐specific management options, including active surveillance, can be tailored to individual patients based on their risk profile. Clinicians should discuss the risks and benefits of each of these options with patients for informed decision-making.
Diagnostic Performance of the Ovarian-Adnexal Reporting and Data System (O-RADS) Ultrasound Risk Score in Women in the United States
Authors: Priyanka Jha, Akshya Gupta, Timothy M. Baran, Katherine E. Maturen, Krupa Patel-Lippmann, Hanna M. Zafar, Aya Kamaya, Neha Antil, Lisa Barroilhet, Elizabeth A. Sadowski
Journal: JAMA Network Open (2022)

The American College of Radiology (ACR) Ovarian-Adnexal Reporting and Data System (O-RADS) ultrasound (US) risk scoring system has been studied in a selected population of women referred for suspected or known adnexal lesions. This population has a higher frequency of malignant neoplasms than women presenting to radiology departments for pelvic ultrasonography for a variety of indications, potentially impacting the diagnostic performance of the risk scoring system.To evaluate the risk of malignant neoplasm and diagnostic performance of O-RADS US risk scoring system in a multi-institutional, nonselected cohort.This multi-institutional cohort study included a population of nonselected women in the United States who presented to radiology departments for routine pelvic ultrasonography between 2011 and 2014, with pathology confirmation imaging follow up or 2 years of clinical follow up.Analysis of 1014 adnexal lesions using the O-RADS US risk stratification system.Frequency of ovarian cancer and diagnostic performance of the O-RADS US risk stratification system.This study included 913 women with 1014 adnexal lesions. The mean (SD) age of the patients was 42.4 (13.9 years), and 674 of 913 (73.8%) were premenopausal. The overall frequency of malignant neoplasm was 8.4% (85 of 1014 adnexal lesions). The frequency of malignant neoplasm for O-RADS US 2 was 0.5% (3 of 657 lesions; <1% expected); O-RADS US 3, 4.5% (5 of 112 lesions; <10% expected); O-RADS US 4, 11.6% (18 of 155; 10%-50% expected); and O-RADS 5, 65.6% (59 of 90 lesions; >50% expected). O-RADS US 4 was the optimum cutoff for diagnosing cancer with sensitivity of 90.6% (95% CI, 82.3%-95.9%), specificity of 81.9% (95% CI, 79.3%-84.3%), positive predictive value of 31.4% (95% CI, 25.7%-37.7%) and negative predictive value of 99.0% (95% CI, 98.0%-99.6%).In this cohort study of a nonselected patient population, the O-RADS US risk stratification system performed within the expected range as published by the ACR O-RADS US committee. The frequency of malignant neoplasm was at the lower end of the published range, partially because of the lower prevalence of cancer in a nonselected population. However, a high negative predictive value was maintained, and when a lesion can be classified as an O-RADS US 2, the risk of cancer is low, which is reassuring for both clinician and patient.
Surgical sperm retrieval and assisted conception outcomes in patients with Klinefelter syndrome with /without hormone stimulation
Authors: S. Rintoul-Hoad, A. Reekhaye, K. Briggs, P. Carroll, D. Prezzi, A. El-Shirif, Y. Kopeika, R. Sandher, M. Shabbir, T. Yap
Journal: European Urology (2022)
RARE-19. Molecular characterization and treatment response of metastatic DIA/DIG
Authors: James Petropoulos, Melanie Finkbeiner, Zarina Assis, Clare Gallagher, Walter Hader, Jennifer Chan, Douglas Strother, Lucie Lafay-Cousin
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Desmoplastic infantile astrocytoma (DIA) and desmoplastic infantile ganglioglioma (DIG) are glioneuronal tumors of early childhood. Surgical resection is usually sufficient to cure these benign tumors. The presence of metastatic seeding is rare and has been reported as an adverse prognostic factor. We present 2 cases of young children with recurrent metastatic DIA/DIG to describe their presentation, therapeutic management and outcome and to highlight the importance of molecular characterization of these rare tumors to guide adjuvant therapy. CASES DESCRIPTION: The first patient developed metastatic recurrence after initial gross total resection (GTR) of a localized DIG. The disseminated relapse was treated with monthly carboplatin and vincristine (CB/VCR). Complete response was achieved after 15 cycles and the patient has remained in continuous complete remission for 5 years. Post hoc molecular analysis of the tumor revealed a BRAF-RDX fusion. The second patient presented with a disseminated intraventricular relapse following an incomplete resection of a DIA associated with a SPECC1L-NTRK2 fusion. The patient received 2 cycles of CB/VCR with minimal response and was then switched to Larotrectinib leading to a very good partial response (VGPR) 3 months into therapy and has remained on treatment since then with significant clinical improvement. DISCUSSION/ CONCLUSION: In our 2 cases, metastatic recurrence was responsive to adjuvant therapy leading to complete response with conventional chemotherapy in the first one and to VGPR with NTRK inhibitor in the second patient. Early molecular characterization of these benign tumors is critical in case of incomplete resection or metastatic seeding to widen therapeutic options and maximize chance of cure. Response with NTRK inhibitor appears rapid and significant but the total duration of treatment and sustainability of response after discontinuation remain unknown.
The Opioid Crisis—Not Just Opioids Anymore
Authors: Jeffrey Brent, Stephanie T. Weiss
Journal: JAMA Network Open (2022)

Penn Whitley, BA; Leah LaRue, PharmD, CMPP, PMP; Soledad A. Fernandez, PhD; Steven D. Passik, PhD; Eric Dawson, PharmD; Rebecca D. Jackson, MD
Assessing the role of high-resolution micro-ultrasound among patients with a negative multiparametric MRI and a persistent suspicion of prostate cancer
Authors: P.P. Avolio, V. Fasulo, M. Paciotti, N. Frego, P. Diana, D. Maffei, R. Contieri, A. Uleri, E. Beatrici, C. Saitta, A. Saita, M. Lazzeri, R. Hurle, P. Casale, N.M. Buffi, G. Lughezzani
Journal: European Urology (2022)
Establishment and characterization of two novel patient-derived organoid xenograft models of advanced prostate cancer
Authors: R. Servant, Z. Diamantopoulou, M. Garioni, L. Roma, T. Vlajnic, A.J. Templeton, H. Pueschel, S. Piscuoglio, N. Aceto, L. Bubendorf, H. Seifert, C.A. Rentsch, C. Le Magnen
Journal: European Urology (2022)
Has the introduction of mpMRI in the diagnostic pathway of prostate cancer led to improved oncological outcomes after radical prostatectomy? Result from a large single-institutional series
Authors: A. Stabile, E. Mazzone, G. Rosiello, G. Sorce, F. Barletta, L. Nocera, V. Cucchiara, E. Zaffuto, F. Dehò, D. Cannoletta, A. Pellegrino, M. De Angelis, S. Scuderi, N. Suardi, N. Fossati, A. Esposito, F. De Cobelli, G. Brembilla, S. Shariat, G. Gandaglia, F. Montorsi, A. Briganti
Journal: European Urology (2022)
In situ-transition nanozyme triggered by tumor microenvironment boosts synergistic cancer radio-/chemotherapy through disrupting redox homeostasis
Authors: Zhongwen Yuan, Xinxin Liu, Jiabao Ling, Guanning Huang, Jiarun Huang, Xueqiong Zhu, Lizhen He, Tianfeng Chen
Journal: Biomaterials (2022)
Effectiveness of NEPA, an oral fixed-dose combination of NEtupitant and PAlonosetron in the prevention of chemotherapy-induced nausea-vomiting in patient receiving highly emetogenic chemotherapy regimens.
Authors: Amit Y Jadhav, Sudeep Gupta, Ghanashyam Biswas, Chandrakanth MV, Palanki Satya Dattatreya, Boben Thomas, Sumant Gupta, Sagar B Bhagat, Saiprasad Patil, Hanmant B Barkate
Journal: Journal of Clinical Oncology (2022)

e24090 Background: Patients receiving Highly Emetogenic chemotherapy (HEC) are &gt; 90% risk of nausea-vomiting due to the drug's emetogenic potential and patient-related factors such as young age, female gender, low/no alcohol, H/O morning sickness and use of alternative medications. The current study was designed to assess the effectiveness of NEPA in patients receiving HEC in a real-world setting in India. Methods: An open-label, single-arm, prospective study among chemonaive patients was conducted across six centers from April 2019 to December 2021 after approval from each institutional ethics committee (CTRI/2020/02/023586). Complete response and treatment-emergent adverse events were the primary endpoints. Secondary endpoints included completion protection, complete control and severity of nausea. Results: HEC regimens were prescribed in 289 of the 360 patients enrolled in the study. Most common HEC regimen was Anthracycline-Cyclophosphamide (44.2%) followed by Paclitaxel-Carboplatin (17.9%). Average age of study population was 52.8±9.8 yrs. with male: female ratio of 1:2.1. Hypertension (17.6%) and diabetes (12.4%) were common comorbidities. Complete response in acute, delayed and overall phases were 94.4%, 94.8%, and 92.7% respectively. In overall phase, complete protection and complete control was 86.8% and 77.5% respectively. Mild, moderate and severe nausea were reported in 11.7%, 7.6%, and 2.4%, patients respectively. Adverse events were seen in 10(3.4%) patients, with leg pain being the most common 3(0.8%). One serious adverse event, unrelated to the study drug was reported. Conclusions: NEPA was effective and well tolerated in patients on a HEC regimen in the acute, delayed and overall phases with a completed response rate of &gt; 90%. Clinical trial information: CTRI/2020/02/023586. [Table: see text]
Management of Growth Disorders in Puberty: GH, GnRHa, and Aromatase Inhibitors: A Clinical Review
Authors: Nelly Mauras, Judith Ross, Veronica Mericq
Journal: Endocrine Reviews (2022)

Abstract Pubertal children with significant growth retardation represent a considerable therapeutic challenge. In growth hormone (GH) deficiency, and in those without identifiable pathologies (idiopathic short stature), the impact of using GH is significantly hindered by the relentless tempo of bone age acceleration caused by sex steroids, limiting time available for growth. Estrogen principally modulates epiphyseal fusion in females and males. GH production rates and growth velocity more than double during puberty, and high-dose GH use has shown dose-dependent increases in linear growth, but also can raise insulin-like growth factor I concentrations supraphysiologically, and increase treatment costs. Gonadotropin-releasing hormone analogs (GnRHas) suppress physiologic puberty, and when used in combination with GH can meaningfully increase height potential in males and females while rendering adolescents temporarily hypogonadal at a critical time in development. Aromatase inhibitors (AIs) block androgen to estrogen conversion, slowing down growth plate fusion, while allowing normal virilization in males and stimulating longitudinal bone growth via androgen receptor effects on the growth plate. Here, we review the physiology of pubertal growth, estrogen and androgen action on the epiphyses, and the therapeutic impact of GH, alone and in combination with GnRHa and with AIs. The pharmacology of potent oral AIs, and pivotal work on their efficacy and safety in children is also reviewed. Time-limited use of AIs is a viable alternative to promote growth in pubertal males, particularly combined with GH. Use of targeted growth-promoting therapies in adolescence must consider the impact of sex steroids on growth plate fusion, and treatment should be individualized.